Register-based study suggests a slightly increased risk of meningiomas in women using hormonal contraception containing a progestogen

A study of 25 years of data from Danish women aged 15-59 suggests that meningiomas (tumours of the meninges) may be a very rare side effect of contraceptives containing a progestogen. The Danish Medicines Agency is therefore raising a safety signal in the European Pharmacovigilance Risk Assessment Committee (PRAC).

The Danish Medicines Agency has carried out a large register-based study using data from more than 3 million Danish women to investigate whether there may be an increased risk of meningiomas associated with the use of hormonal contraception containing a progestogen.

The study suggests a slightly increased risk of developing meningiomas (tumours of the meninges) in women who have used either combination contraceptive pills, progestogen-only pills, intrauterine devices or contraceptive injection with certain types of progestogens, compared with women who have not used hormonal contraception.

The increased risk is greatest while the woman is using the contraceptive and with long-term use - that is, when the contraception has been used for at least five years. If more than five years have passed since the woman stopped using the contraceptive, the study no longer finds an increased risk.

Meningiomas are usually benign (90 percent) but may nevertheless be serious because of their location close to the brain. Overall, around 750 people in Denmark are diagnosed with meningiomas each year. They occur 2-3 times more often in women than in men, and the risk increases with age.

Known risk with other medicines

The development of meningiomas is already known to be a rare side effect of the contraceptive injection, as well as of some other medicines that also contain a progestogen but are used for purposes other than contraception. For example, it is a known side effect of some medicines for prostate cancer and some medicines for women who have endometriosis or very heavy, painful or irregular periods.

The Danish Medicines Agency has previously, together with its European colleagues in PRAC, assessed the risk of developing meningioma during treatment with progestogen-containing medicines as part of the continuous drug safety surveillance. Until now, the available knowledge about most progestogens has been too limited to establish or rule out a possible risk. The Agency therefore considered it relevant to investigate the risk using a register-based study.

'In Denmark, we have access to very high-quality register data, and we were therefore able to carry out a large study with data spanning more than 25 years across all the progestogen-containing contraceptives that have been used in Denmark. This means that we have a well-documented and statistically significant result that contributes to the overall knowledge about progestogens,' says Line Michan, Head of Unit at the Danish Medicines Agency.

The study includes all the progestogens (a total of 22 different progestogen formulations) used for contraception that were sold in Denmark between 2000 and 2024. The study presents results for 12 types of progestogen for which there were sufficient data, and finds an increased risk for 8 of these.

Some products are widely used, while others are only used to a small extent in Denmark. There are also authorised progestogens that have been sold in other countries but have not been marketed in Denmark. The Danish Medicines Agency has therefore not been able to estimate the risk for all progestogen-containing contraceptives across the entire European market, but the Agency considers that the result may be relevant to the whole class of medicines.

'Although the study does not find an increased risk for all progestogens, it finds an increased risk across the so-called "generations" of progestogens and across the chemical subdivision of progestogens. This may indicate that the risk applies to the entire class of medicines, where the available data suggest that meningiomas may occur as a very rare side effect,' explains Line Michan.

The pharmacovigilance committee will evaluate the potential association

A considerable amount of research has previously been carried out for this topic, with some studies showing an increased risk of meningioma after treatment with a progestogen-containing contraceptive product, while others do not find an increased risk. However, most earlier studies primarily examined the risk for groups of progestogens (for example, contraceptive pills as one overall group) rather than focusing on the individual active substances, as the Danish Medicines Agency's study has done.

The scientific journal JAMA Network Open has published the register-based study, and because it adds new knowledge to the topic, the Danish Medicines Agency will, on the basis of the study, raise a so-called safety signal to the European Pharmacovigilance Risk Assessment Committee (PRAC) to have the overall evidence assessed.

'If PRAC considers that, taken together, there is sufficient evidence of an association, this could ultimately lead to the risk of meningiomas being included as a side effect in the package leaflet and the Summary of Product Characteristics (SmPC). But first the committee must assess the study and compare it with other evidence for the topic to see whether the overall evidence shows the same trend. In addition, the companies that market progestogens will be involved in the evaluation,' says Line Michan.

She stresses that, although an increased risk is seen with the use of hormonal contraception, the absolute risk for the individual woman remains very low.

'We do not recommend that people change their behaviour and decide against contraception, because at the individual level it is a very small risk and an extremely rare side effect. But when using medicines, it is always important to consider and be aware of what side effects may occur, and - as with any other illness - you should always see your doctor if you develop any symptoms that require medical assessment.'

Link

Contraceptive Progestogens and Incident Meningioma (jamanetwork.com)